U.S. Pat. No. 4,289,787 describes a group of phenylalkyl quaternary ammonium salts that are useful as antiarrhythmic agents and are effective in prolonging the action potential duration of cardiac tissue. One compound within this group, namely 4-chloro-N,N-diethyl-N-heptylbenzenebutanaminium phosphate, has undergone extensive biological evaluations and is now known generically as clofilium. A summary of the efficacy of this compound is set forth in New Drugs Annual: Cardiovascular Drugs, Vol. 2, 103, edited by Alexander Scriabine, Raven Press, New York (1984).
While clofilium and quaternary ammonium salts similar in structure to clofilium have proved to be extremely potent antiarrhythmic agents, their clinical usefulness has been limited in part because of their marginal oral bioavailability. It is now believed that the relatively low order of oral bioavailability is attributable in part to the charged nature of the quaternary ammonium portion of the molecule.
While the quaternary ammonium compounds disclosed in U.S. Pat. No. 4,289,787 are in general much more potent antiarrhythmic agents than the corresponding secondary and tertiary amines from which they are derived, one particular group of secondary and tertiary amines has been reported to possess unexpectedly good antiarrhythmic activity compared to agents such as clofilium; see U.S. Pat. No. 4,336,269. The specific group of compounds claimed in that patent are phenylalkylamines wherein the phenyl group is required to bear a para-nitro substituent.
While the para-nitro phenylalkylamines are extremely potent antiarrhythmic agents which prolong the action potential duration of cardiac tissue, it has now been learned that such nitro compounds are also rapidly metabolized by some biological systems, such as by conscious dog models, to agents having significantly diminished efficacy. One possible product of metabolism may be the corresponding amino substituted phenylalkylamine, which is known to be substantially inactive as an antiarrhythmic agent.
We have now discovered a group of phenyalkylamines that are potent antiarrhythmic agents, that appear to have good oral bioavailability properties and that do not appear to be subject to as rapid inactivation in vivo as the previously described agents. It therefore is an object of this invention to provide a new class of phenylalkylamines that can be employed in the clinical treatment of re-entrant cardiac arrhythmias.